Process for preparing 1,2,5-thiadiazol-3-ylacetic acid from 3-methyl-1,2,5-thiadiazole

ABSTRACT

A novel process for preparing thiadiazole aliphatic carboxylic acids and the lower alkyl esters of the following formula:

Kariyone et al.

Oct. 7, 1975 l l PROCESS FOR PREPARING 1,2,5-THlADlAZOL-3-YLACET1C ACIDFROM S-METHYL-1,2,5-THIADIAZOLE {75] Inventors: Kazuo Kariyone, Kyoto;Kunihiko Tanaka, Toyonaka; Keiji Takai, Nara, all of Japan [73]Assignee: Fujisawa Pharmaceutical Co., Ltd.,

Osaka, Japan [22} Filed: June 25,1973

[2]] Appl. No: 372,796

[30] Foreign Application Priority Data June 27, I972 Japan 47-64625 [52]US. Cl H 260/302 D; 204/158 [5 1] Int. Cl. C07D 285/10 (58] Field ofSearch 260/302 D [56] References Cited UNITED STATES PATENTS 3,488,3601/1970 Weinslock et al, 260/302 D OTHER PUBLICATIONS Katritzky et al.,(eds), Advances in Heterocidic Chemistry. Vol. 9, Academic Press. N.Y..1968, p.

Primary Examiner-Richard J. Gallagher Attorney, Agent, or Firm-Liddy,Sullivan, Hart, Daniels & Stemple l5 7 ABSTRACT A novel process forpreparing thiadiazole aliphatic carboxylic acids and the lower alkylesters of the following formula:

wherein R is a thiadiazolyl group, R is a lower alkylidene group and Ris hydrogen or a lower alkyl group, which comprises reacting a loweralkyl substituted thiadiazole of the formula: R,R, wherein R is asdefined above and R is a lower alkyl group, with a halogenating agent,reacting the resulting m0nohalo(lower)alkyl substituted thiadiazole ofthe formula: R,R- X wherein R and R are as defined above and X is ahalogen, with hydrocyanic acid or its salt, and hydrolyzing theresulting cyano(lower)alkyl substituted thiadiazole of the formula: R,RCN wherein R, and R are as defined above, optionally prior to thehydrolysis the cyano compound being treated with a lower alcohol.

5 Claims, No Drawings PROCESS FOR PREPARING l ,2,5-THIADlAZOL-3-YLACETICACID FROM B-METHYL-l ,2,5-THIADIAZOLE The present invention relates to anovel process for preparing thiadiazole aliphatic carboxylic acids orthe lower alkyl esters thereof. More particularly, it relates to a novelprocess for preparing thiadiazole aliphatic carboxylic acids or thelower alkyl esters of the following formula:

(I wwherein R is a thiadiazolyl group, R is a lower alkylidene group andR is hydrogen or a lower alkyl group.

In the specification. the thiadiazolyl group for R meansl,2,3-thiadiazoly, l,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, orl,2,5-thiadiazolyl; the lower alkylidene group for R means a loweralkylidene having one to four carbon atoms, such as methylene.ethylidene, propylidene or butylidene; and the lower alkyl group for Rmeans a lower alkyl having one to four carbon atoms. such as methyl,ethyl. propyl, isopropyl, butyl, or isobutyl.

Among the present compounds, 1,2,5-thiadiazol-3- acetic acid has beendescribed in US. Pat. No. 3,322,749, and it has been prepared by (l)treating 2,1,3-benzothiadiazole with a mixture of concentrated nitricacid and concentrated sulfuric acid, (2) reacting the resulting4-nitro-2, l ,3-benzothiadiazole with potassium permanganate, reactingthe resultant with concentrated nitric acid and silver nitrate to givesilver 1,2- ,S-thiadiazole-3,4-dicarboxylate, and treating the resultantwith hydrogen sulfide to give the corresponding dicarboxylic acid, (3)treating the dicarboxylic acid with heat to give the correspondingmonoearboxylic acid, (4) reacting the resultant with thionyl chloride togive the corresponding acid chloride, (5) treating the resultant withdiazomethane, (6) reacting the resulting 3-diazoacetyl compound withbenzylalcohol and hydrolyzing the resulting benzyl 1,2,5-thiadiazol-3-acetate. According to the known method, many steps are needed for thepreparation of the desired l,2,5- thiadiazol-3-acetic acid and the yieldis considerably low.

It has been studied to find a more advantageous process for thepreparation of thiadiazole aliphatic carboxylic acids or the lower alkylesters thereof, and there has now been found a novel process for thepreparation of the desired compounds in a few steps and in higher yield.

According to the present invention, the desired thiadiazole aliphaticcarboxylic acids and the lower alkyl esters thereof (I) can be preparedby reacting a lower alkyl substituted thiadiazole of the formula:

I") wherein R, is as defined above and R is a lower alkyl group such asmethyl, ethyl, propyl or butyl, with a halogenating agent to give amonohalo(lower)alkyl substituted thiadiazole of the formula:

wherein R, and R are as defined above and X is halogen, such aschlorine, bromine or iodine, reacting the resultant (III) withhydrocyanic acid or a salt thereof to give a cyano (lower)-alkylsubstituted thiadiazole of the formula:

wherein R R2 are as defined above, and hydrolyzing the resulting cyanocompound (lV), optionally prior to the hydrolysis said cyano compound(IV) being treated with a lower alcohol.

The starting lower alkyl substituted thiadiazoles (II) are knowncompounds and for instance, 3-alkyl-l,2,5- thiadiazole is prepared by amethod described in Journal 0f the Organic Chemistry, Vol. 32, pages2823- 2829 (1967).

In the present process, the first step comprises the reaction of a loweralkyl substituted thiadiazole (II) with a halogenating agent. As thehalogenating agent, there may be used any agent which can be used forhalogenation of an alkyl group, for instance, halogen (eig. chlorine,bromine, or iodine), halogen halide (e.g. iodine chloride, iodinetrichloride, or iodine bromide), sulfuryl halide (e.g. sulfurylchloride, or sulfuryl bromide), hypohalogenous acid salt or ester (e.g.sodium hypochlorite, or ethyl hypochlorite and N-haloacid amide or imide(e.g. N-chlorourea, N-bromoacetamide, l,3,5-trichloro-s-triazine-2,4,6-( l H, 3H, 5H)-trione, N- bromosuccinimide,or N-bromophthalimide).

The reaction may he usually carried out in a solvent such astetrachloromethane, chloroform, methylene chloride or ethyleneehloride,or other inert solvent. The reaction is preferably carried out in thepresence ofa reaction accelerator, such as diaroyl peroxide (e.g.benzoyl peroxide), dialkylperoxide (e.g. di-t-butyl peroxide), esterperoxide (e.g. t-butyl perbenzoate), or an aliphatic azo compound (e.g.azobis-isobutyronitrile), or under the irradiation of light. Thesuitable reaction accelerator is optionally selected in accordance withthe kind of halogenating agent. There is no limitation to the reactiontemperature and it may be optionally carried out at room temperature orat an elevated temperature in accordance with the kind of the startingmaterial (I) and the halogenating agent, but it is not suitable to do atso high temperature since it results in occurrence of side reaction. Thehalogenating agent may be preferably used in an amount of about onechemical equivalent to the starting material (II). In the abovereaction, there may be occasionally produced dihalogenated ortrihalogenated compound in addition to the desired monohalo( lower)alkylsubstituted thiadiazole (Ill), but the monohalo'genated compound (Ill)may be used in the subsequent step without isolation.

The halo(lower)alkyl substituted thiadiazole (Ill) thus obtained may bereacted with hydrocyanic acid or its salt to give a cyano(lower)alkylsubstituted thiadiazole (IV). When hydrocyanic acid is used, thereaction may be preferably carried out in the presence of an inorganicor organic basic condensing agent, such as alkali metal (e.g. sodium, orpotassium), alkaline earth metal (e.g. magnesium, or calcium), orhydroxide, alkoxide, amide, hydride, or carbonate of the alkali metal oralkaline earth metal, or an organic amine (e.g. dimethylamine, ortriethylamine). The hydrocyanic acid can be used also in gaseous form.As the salt of the hydrocyanic acid, there may be used salts with anymetal, such as an alkali metal or an alkaline earch metal as mentionedabove or any other metal, and further the ammonium salt or a salt withthe amine as mentioned above.

The above reaction may be carried out in a solvent, such as acetone,benzene, methanol, ethanol, dimethylformamide, or other inert solvent.There is no specific limitation to the reaction temperature, but it canbe done enough even at room temperature.

The cyano(lower)alkyl substituted thiadiazole (IV) may be isolated, butmay be used in the subsequent hydrolysis without isolation.

The cyano(lower)alkyl substituted thiadiazole (IV) obtained above ishydrolyzed to give the desired thiadiazole aliphatic carboxylic acid (I)wherein R is hydrogen.

The hydrolysis is usually carried out in the presence of an acid or analkali. The suitable examples of the acid may be an inorganic acid suchas hydrochloric acid or sulfuric acid, and the suitable examples of thealkali may be an alkali metal hydroxide such as sodium hydroxide orpotassium hydroxide, or an alkaline earth metal hydroxide such ascalcium hydroxide, but any other alkali may be also used. The reactionmay be carried out in a solvent such as an alcohol (e.g. methanol,ethanol), ether, dioxane, or other inert solvent. There is no specificlimitation to the reaction temperature, but it may he usually carriedout at room temperature or at an elevated temperature.

When the cyano(lower)alkyl substituted thiadiazole (IV) is reacted witha lower alcohol and then the resultant is hydrolyzed, the desiredcompound (I) wherein R is a lower alkyl can be obtained. The loweralcohol means an aliphatic alcohol such as, methanol, ethanol, propanol,isopropanol, butanol, or isobutanol. The reaction of the cyano compound(IV) with the lower alcohol is preferably carried out in the presence ofan acid catalyst, such as hydrochloric acid, aromatic sulfonic acid, orboron fluoride. The reaction may be carried out in a solvent such asether or dioxane, but the reactant lower alcohol may be usually usedalso as the solvent. According to the reaction, there may be obtained animinoether compound under anhydrous condition. However, if water ispresent in the reaction system, the iminoether compound may behydrolyzed therewith to give the desired thiadiazole aliphaticcarboxylic acid lower alkyl ester (1) wherein R, is a lower alkyl. Thus,the iminoether compound may be easily hydrolyzed merely by treating itwith water under cooling or at room temperature to an elevatedtemperature, but any other hydrolysis may be also applicable.

The thiadiazole aliphatic carboxylic acid lower alkyl ester obtainedabove may be hydrolyzed under the sim ilar conditions to those in thehydrolysis of the cyano(- lower)-alkyl substituted thiadiazole (IV) togive the free thiadiazole aliphatic carboxylic acid (I) wherein R ishydrogen.

The present invention is illustrated by the following examples, but notlimited thereto.

EXAMPLE 1 a. Preparation of 3-bromomethyl-l ,2,5-thiadiazole:

Into tetrachloromethane (100 ml) were suspended 3-methyll,2,5-thiadiazole g), N-bromosuccinimide l 7. 8 b) and01,01-azobisisobutyronitrile l g), and the mixture was refluxed for 45minutes under stirring.

After cooling, the reaction mixture was filtered to remove the insolublematerial, and the filtrate was concentrated under reduced pressure. Theresidual liquid material was distilled under reduced pressure to giveFraction (A) (9.9 g) having a boiling point of 8285C/7 mmHg whichcontained 3-bromomethyl- 1,2,5-thiadiazole (8.4 g), and Fraction (B)(2.3 g) having a boiling point of l()0 103C/7 mmHg which contained saidcompound (0.34 g).

IR. spectrum (liquid film): Fraction (A) Fraction (B) 3080 cm" 3080 cm"(CH in l,2,5-thiadiazole ring) 792 cm 793 cm l.2.5-thiadiazole ring)72-4 cm 721 cm (CBr) UV. spectrum ()5 7r ethanol). Fraction (A) Fraction(B) Amax 262.5 mp. Amax 264 my.

IR. spectrum (liquid film):

3080 cm" (CH in I 2,S-thiadiazole ring) 792 cm" 1,2,S-thiadiazole ring)763, 740 cm (CCI) LLV. spectrum /r ethanol);

Amax 259 mp.

EXAMPLE 2 Preparation of 3-cyanomethyI-l ,2,5-thiadiazole:

To a solution of Fraction (A) obtained in Example l, (a) l0 g:containing 0.05 mol 3-bromoethyl-l,2,5- thiadiazole) indimethylformamide ml) was grad ually added powdery sodium cyanide (2.5g) at room temperature over a period of 30 minutes, and the mixture wasstirred for IS minutes. The reaction mixture was poured onto ice-water(200 ml) and extracted with benzene. The extract was washed with water,dried over magnesium sulfate and concentrated. The concentrated liquidwas subjected to alumina column chromatography and eluted with benzene.The fraction containing 3-cyanomethyl-l,2,5-thiadiazole was separatedand distilled to remove the solvent to give colorless tabular crystals(2,4 g) of 3-cyanomethyl-l,2,5- thiadiazole, M.P. 35 36C.

IR. spectrum (nujol UV. spectrum (95 71 ethanol):

Amax 256 my, 259 mu EXAMPLE 3 Preparation of l,2,5-thiadiazol-3-aceticacid:

To a solution of 3-chloromethyl-1.2,5-thiadiazole l25 g) indimethylformamidc (200 ml) and methanol (100 ml) was added a catalyticamount of potassium iodide at room temperature under stirring, andthereto was further added in portions powdery sodium cyanide (60 g) in avelocity so as to maintain the mixture at 65C. The mixture was stirredat 60C for 30 minutes. After cooling, the reaction mixture was pouredonto ice-water (500ml). The organic layer was separated and the aqueouslayer was extracted a few times with ethyl acetate. The extracts werecombined with the organic layer and washed with water. The washings werefurther extracted twice with ethyl acetate. The extract was washed withwater and then combined with the above organic layer. The organic layerthus obtained was dried over magnesium sulfate and distilled to removethe solvent to give crude 3-cyanomethyl-l.2,5- thiadiazole as a residue.To the residue were added acetic acid (200 ml) and 50 sulfuric acid (400ml) and the mixture was refluxed for 4 hours under stirring. Thereaction mixture was poured onto ice-water (one liter) and extractedfive times with ethyl acetate (total 1 .5 liter). The extract wasconcentrated under reduced pressure, and to the residue was added 20 7(aqueous sodium hydroxide to make it alkaline. The insoluble material wasremoved by washing with ethyl acetate. The alkaline aqueous solution wasacidified at pH l with concentrated hydrochloric acid, and extractedfour to five times with ethyl acetate (total about l liter). The extractwas washed with small amount of saturated aqueous sodium chloride, driedover magnesium sulfate and distilled to remove the solvent to givecrystalline residue. The residue was recrystallized from benzene to givel 2,S-thiadiazol-3-acetic acid (72 g), M.P. 8U 8lC.

(C0) l 2,5-thiadiazolc ring) EXAMPLE 4 Preparation of ethyll,2,5-thiadiazol-3-acetate:

To a solution of Fraction (A) obtained in Example l, (a) l0 g:containing 0.05 mol 3-br0moethyl-l,2,5- thiadiazole) indimethylformamide 100 ml) was gradually added powdery sodium cyanide(2.5 g) at room temperature over a period of 30 minutes under stirring.and the mixture was stirred for minutes. The reaction mixture was pouredonto ice-water (200 ml), and extracted with ether. The extract waswashed with water, dried over magnesium sulfate and concentrated tillthe total amount became about 50 ml. To the concentrated liquid wasadded ethanol (2,3 g) and the mixture was saturated with dry hydrogenchloride gas at 5C or less under stirring. The mixture was distilledunder reduced pressure to remove the solvent. The resulting crystallineresidue was dissolved in water and extracted with ethyl acetate. Theextract was dried over magnesium sulfate and distilled to remove thesolvent. The residue was distilled under reduced pressure to give 6.colorless liquid ethyl l,2,5-thiadiazol-3-acetate (2.5 g), B. P. 108-ll3C/l0- ll mml-lg.

IR. spectrum [liquid film):

3090 cm (CH in l,2.5-thiadiazole ring) I738 cm (CO) 79] cml,2,5-thiadiazole ring) EXAMPLE 5 Preparation of1,2,5-thiadiazol-3-acetic acid:

A mixture of ethyl l.2 5-thiadiazol-3-acetate (17.2 g), potassiumhydroxide (6.5 g), methanol ml) and small amount of water was allowed tostand at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure. The resulting crystalline residuewas dissolved in small amount of water and washed with ether (I00 ml).The aqueous layer was made acidic at pH 1 with l0 hydrochloric acid andextracted twice with ether (each 100 ml). The extract was washed withaqueous sodium chloride and dried over magnesium sulfate and distilledto remove the solvent to give yellow crystalline residue (10.3 g). Theresidue was recrystallized from benzene to give flaks (6.0 g) ofl,2,5-thiadiazol-3-acetic acid, M.P. 77

What is claimed is:

l. A process for preparing the compound of the formula which comprisesthe steps:

a. halogenating the compound with a halogenating agent selected from thegroup consisting of N-bromo-succinimide and1,3,5-trichloro-striazine-2,4,6-( 1H, 3H, SH)-trione in the presence ofa, a-azobisisobutyronitrile to form the compound of the formula cruxwherein X is bromine or chlorine,

b. treating the compound UT ca x wherein X is as defined above, withhydrogen cyanide four carbon atoms to form an ester of the formula or asalt thereof to form the nitrile of the formula WCHZCN WCH-ICQR \j andthen hydrolyzing said ester to the acid H) and c-l. hydrolyzing saidnitrile by treatment with an acid c co -i selected from the groupconsisting of hydrochloric and sulfuric to the compound z- 2. A processaccording to claim 1 wherein the salt of hydrogen cyanide is an alkalimetal. 7 3. A process according to claim 2 wherein the alkali s metalcyanide is sodium cyanide.

4. A process according to claim 3 wherein the haloor genating agent isN-bromo-succinimide and X is broc-Z. treating said nitrile with a loweralkanol of the mine.

formula 75 5. A process according to claim 3 wherein the halo- R OHgenating agent is l, 3, S-trichloro-s-triazine-2, 4, 6-( lH,

3H, 5H)-trione and X is chlorine. wherein R is a lower alkyl grouphaving from one to

1. A PROCESS FOR PREPARATING THE COMPOUND OF AFORMULA
 2. A process according to claim 1 wherein the salt of hydrogen cyanide is an alkali metal.
 3. A process according to claim 2 wherein the alkali metal cyanide is sodium cyanide.
 4. A process according to claim 3 wherein the halogenating agent is N-bromo-succinimide and X is bromine.
 5. A process according to claim 3 wherein the halogenating agent is 1, 3, 5-trichloro-s-triazine-2, 4, 6-(1H, 3H, 5H)-trione and X is chlorine. 